Cellular fibronectin as a diagnostic marker in stroke and methods of use thereof

Abstract

The present invention relates to methods for the diagnosis and evaluation of stroke and stroke sub-type. A variety of bio-markers are disclosed for assembling a panel for such diagnosis and evaluation. Methods are disclosed for selecting markers and correlating their combined levels with a clinical outcome of interest. In various aspects: the invention provides methods for early detection and differentiation of stroke subtypes, for determining the prognosis of a patient presenting with stroke symptoms, and identifying a patient at risk for hemorrhagic transformation after thrombolyic therapy. Methods are disclosed that provide rapid, sensitive and specific assays to greatly increase the number of patients that can receive beneficial stroke treatment and therapy, and reduce the costs associated with incorrect stroke diagnosis.

Description

RELATED APPLICATIONS [0001] The present application is descended from, and claims benefit of priority of, U.S. provisional patent application No. 60 / 505,606, the contents of which of which are hereby incorporated herein in their entirety, including all tables, figures, and claims. The present application is a continuation-in-part of U.S. utility patent application Ser. No. 10 / 948,834, which application is itself descended from U.S. provisional patent application 60 / 505,606 and 60 / 556,411FIELD OF THE INVENTION [0002] The present invention generally relates to the identification and use of diagnostic markers for cardiovascular disease and cerebral injury. In a various aspects, the present invention particularly relates to methods for (1) the early detection and differentiation of cardiovascular events stroke and transient ischemic attacks, and (2) the identification of individuals at risk for hemorrhagic transformation after both presentation with stroke symptoms and subsequent admini...

AI Technical Summary

Benefits of technology

[0026] In one of its aspects, the invention discloses methods for determining a diagnosis or prognosis related to a cardiac event such as stroke, or for differentiating between stroke sub-type and / or determination of HT. The preferred method includes analyzing a fluid sample obtained from a person who has an unknown diagnosis for the levels of one or more markers specific to the damage caused by said cardiac event. In the case of stroke, these markers would be drawn from the group consisting of markers relating to vascular damage, glial activation, inflammatory mediation, thrombosis, cellular injury, apoptosis, myelin breakdown, and specific and non-specific markers of cerebral injury. The analysis of the preferred method thus more precisely includes identifying one or more markers the presence or amount of which is associated with the diagnosis, prognosis, or differentiation of stroke and / or determination of HT. Once such marker(s) are identified, the next in the method the level of such marker(s) in a sample obtained from a subject of interest can be measured. In certain embodiments of the preferred method, these markers can be compared to a level that is associated with the diagnosis, prognosis, or differentiation of stroke and / or determination of HT. By correlating the subject's marker level(s) to the diagnostic marker level(s), the presence or absence of stroke, and also the probability of future adverse outcomes, etc., in a patient may be rapidly and accurately determined.

[0027] In another of its aspects, the instant invention is embodied in methods for choosing one or more marker(s) for differentiation of stroke and / or determination of HT that together, and as a group, have maximal sensitivity, specificity, and predictive power. Said maximal sensitivity, specificity, and predictive power is in particular realized by choosing one or more markers as constitute a group by process of plotting receiver operator characteristic (ROC) curves for (1) the sensitivity of a particular combination of markers versus (2) specificity for said combination at various cutoff threshold levels. In addition, the instant invention further discloses methods to interpolate the nonlinear correlative effects of one or more markers chosen by any methodology to such that the interaction between markers of said combination of one or more markers promotes maximal sensitivity, specificity, and predictive accuracy in the prediction of any of the occurrence of stroke, identification of stroke subtype, or likelihood of HT.

Problems solved by technology

A stroke may cause sudden weakness, loss of sensation, or difficulty with speaking, seeing, or walking.

Stroke or brain attack is a sudden problem affecting the blood vessels of the brain.

If an artery is blocked, the brain cells (neurons) cannot make enough energy and will eventually stop working.

If the artery remains blocked for more than a few minutes, the brain cells may die.

The most common problem is narrowing of the arteries in the neck or head.

If the arteries become too narrow, blood cells may collect and form blood clots.

These blood clots can block the artery where they are formed (thrombosis), or can dislodge and become trapped in arteries closer to the brain (embolism).

This naturally restricts the flow of blood to the brain and results in almost immediate physical and neurological deficits.

In addition, prior studies have found that the accuracy of stroke identification by medical personnel is modest and variable from one community to another.

Finally, any clinical neurological screening test will be limited by the training and experience of the examiner.

This insensitivity to acute stroke limits its use to post-stroke damage assessment.

However, this takes several hours, and thus is not used for rapid diagnosis of stroke.

However, as a practical issue, most hospitals do not have these specialized and highly expensive MRI services available in the acute setting.

Thus, without a practical and widely available radiological test, the diagnosis of stroke remains largely a clinical decision.

Thrombolytic therapy has been proven to be effective for the treatment of acute ischemic stroke, but the increased risk of hemorrhagic transformation (HT) associated with tissue plasminogen activator (tPA) administration is still of great clinical concern.

However, despite the available data, the underlying molecular mechanisms related to HT after thrombolytic treatment have yet to be fully elucidated.

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